Dr. Don W. Cleveland

Professor of Medicine, Neurosciences, and Cellular and Molecular Medicine

Member,
Ludwig Institute for Cancer Research

CONTRIBUTIONS

SYNOPSIS OF D.W. CLEVELAND’S CONTRIBUTIONS TO SCIENCE

Cleveland has made ground-breaking contributions in the regulation
of assembly of mitotic spindles and chromosome movement. He discovered the microtubule associated protein tau (mutation in which causes
human cognitive disease), the tubulin gene families encoding the major subunits of microtubules, and the first mammalian example of
control of gene expression through regulated RNA instability. He identified components required for microtubule nucleation and anchoring
during spindle assembly. He discovered CENP-E, the centromere-associated, microtubule-motor that he showed to be a microtubule “tip
tracker” essential for powering congression of initially misaligned chromosomes, chromosome attachment at centromeres, and maintenance
ofchromosome congression. Using all purified components, he identified that unattached centromeres/kinetochores initiate a
two step catalytic cascade signaling mechanism that represents the mitotic checkpoint, the cell cycle control mechanism that prevents
errors of chromosome segregation in mitosis. He identified that the meiotic counterpart of the mitotic checkpoint is silenced without
development of interkinetochore tension, thereby uncovering a mechanistic basis for the high error frequency of female meiosis in
mammals.

The centromere is the basic determinant of chromosome inheritance. Unlike genes carried on those chromosomes, however,
centromere position is defined by an epigenetic mark, not by DNA sequence. Cleveland identified the basis for epigenetic inheritance
of centromere identity. He demonstrated it to be chromatin assembled with the histone H3 variant CENP-A, which he showed to be able
to template its own replication through action HJURP, the histone chaperone/chromatin loader he and his team discovered.

In neurons
cell biology, other major contributions emerged from Cleveland’s demonstration that extreme asymmetry of neurons is achieved with
a deformable array of interlinked neurofilaments, microtubules and actin. He showed that disorganization of neurofilaments causes
selective failure of motor neurons in mice and humans. He then demonstrated that similar disease could also arise by a toxicity of
mutant superoxide dismutase unrelated to its normal activity, thereby uncovering the mechanism underlying a major genetic form of
Amyotrophic Lateral Sclerosis (ALS).He also showed that motor neuron death in inherited ALS is non-cell autonomous, requiring
mutant damage to both motor neurons and the neighboring supporting cells. This discovery has wide implications for other major neurodegenerative
diseases, since the inherited forms of each are also caused by widely expressed mutant genes. Cleveland’s findings demonstrated the
attractiveness of stem cell replacement of non-neuronal cells as a viable therapy in ALS

.

SYNOPSIS OF D.W. CLEVELAND’S CONTRIBUTIONS
TO MEDICINE

Cleveland has made field leading discoveries into the causes and treatment of ALS and Huntington’s diseases, with implications
for a set of additional neurodegenerative/ neuromuscular diseases that include spinal muscular atrophy, myotonic dystrophy and Alzheimer’s
and chronic traumatic brain injury. His efforts identified key steps that trigger disease and that accelerate ALS disease progression
from mutation in superoxide dismutase. These findings have redirected efforts at stem cell and gene silencing therapies in ALS. Cleveland
also identified tau, the microtubule associated protein which misaccumulates in intraneuronal tangles in essentially all instances
of Alzheimer’s disease and whose misfolding mediates a slow cell-to-cell spread that is causative of the chronic traumatic encephalopathy
associated with repeated brain injury now recognized to be prominent in athletics.

Cleveland developed a pair of gene silencing
therapies widely applicable in human neurodegenerative disease. His initial approach established utility of “designer DNA drugs” (short
single stranded DNAs) that mediate catalytic, RNase H-dependent degradation of the RNA encoded by any selected gene. He demonstrated
that single dose infusion of such designer DNA drugs produces durable efficacy (lasting more than three months) throughout the entirety
of the rodent and non-human nervous systems. An initial application was for an inherited form of ALS and which entered clinical trial
in 2010. In 2013, an extension of this approach entered clinical trial for myotonic dystrophy. Additional trials initiated for Huntington’s
disease in 2015 and ALS in 2016, and one is anticipated to initiate early in 2017 for the most frequent cause of ALS and Frontal Temporal
Degeneration (FTD), hexanucleotide expansion in the C9orf72 gene.

Extensions for development of clinical trials for silencing
genes central to Alzheimer’s and Parkinson’s diseases, chronic brain injury, and a set of ataxias are ongoing. An additional application
is in trial with a designer DNA drug chemically modified so that it is not recognized by RNase H (and therefore does not stimulate
RNA degradation) but acts to correct an RNA splicing abnormality in spinal muscular atrophy, one of the most abundant genetic diseases
of children.

Cleveland has pioneered additional gene silencing or gene replacement therapies for human nervous system disease
using adenoassociated virus (AAV). He and his colleagues have shown remarkably broad delivery within the nervous system and they are
now developing this for human clinical trial expected to initiate in 2017 using AAV encoding a short hairpin RNA which acts with the
RNA-induced silencing complex (RISC) to trigger degradation of the RNA encoded by a mutated superoxide dismutase gene causative of
inherited ALS.

Lastly, with his corporate partner Ionis Pharmaceuticals, Cleveland developed the first synthetic CRISPR RNA,
demonstrating that it can direct and activate transient, DNA site sequence-specific Cas9 nuclease activity which will cleave and inactivate
a target gene. This approach is now in development for therapy combining AAV gene delivery and synthetic CRISPR infusion for gene
silencing or correction.

Aneuploidy - acquisition of a chromosome content other than a multiple of the haploid number – has long
been known to be a frequent component of tumorigenesis. By generating mice that develop aneuploidy at high rates, Cleveland tested
the 100 year old hypothesis that aneuploidy drives tumorigenesis. He demonstrated that aneuploidy drives tumorigenesis in some genetic
contexts, but suppresses it when combined with tumorigenic mechanisms that independently generate high levels of aneuploidy. Cleveland
also discovered the centromere motor CENP-E. His demonstration that inhibition of it induces chronic mitotic arrest followed by cell
death for a variety of tumor cells, has enabled development of inhibitors of the CENP-E motor. GlaxoSmithKline and Cytokinetics have
taken CENP-E inhibitors to clinical trial for human solid tumors.

AWARDS AND HONORS

The Breakthrough Prize in life sciences or
mathematics, 2018

Elected Member, National Academy of Sciences, 2006

Elected Fellow, American Academy of Arts and Sciences, 2006

Elected
Fellow, American Association for the Advancement of Science, 2009

Elected Member, The National Academy of Medicine, 2012

Elected Fellow,
American Academy of Microbiology, 2006

President, American Society for Cell Biology, 2013

Katharine Berkan Judd Award, Memorial Sloan
Kettering, 2012

Wings Over Wall Street and MDA Outstanding Scientist, October 2007

Outstanding Scientist Award, Playing to Win for
Life Foundation, September 2004

Sheila Essey Prize, American Academy of Neurology and the ALS Association, April, 1999